Many clinical and experimental techniques to treat cancer, such as cytokine therapy, chemotherapy, radiotherapy, cellular immunotherapy, and photodynamic therapy (PDT), promote the formation of reactive oxygen species (ROS). ROS include superoxide anions, hydrogen peroxide, and hydroxyl radicals. ROS participate in the formation of other reactive species. For example, superoxide reacts with nitric oxide to form peroxynitrite, and hydroxyl radicals remove hydrogen atoms from organic compounds to yield reactive carbon-centered radicals. ROS cause oxidative stress leading to cellular damage and cell death. Cytokines, such as tumor necrosis factor, cause apoptotic tumor cell death via intracellular hydroxyl radical production (Schulze-Osthoff et al., J. Biol. Chem. 267:5317-23 (1992) and Yamauchi et al., Cancer Res. 49:1671-5 (1989)). Many chemotherapeutic drugs induce the production of hydroxyl radicals (Doroshow, J. H., Proc. Natl. Acad. Sci. USA 83:4514-8 (1986).), with 56 of 132 FDA-approved anti-cancer drugs promoting oxidative stress (Chen et al., Mol. Interv. 7:147-56 (2007)). Radiotherapy causes the formation of hydroxyl radicals by water ionization (Riley, P. A., Int. J. Radiat. Biol. 65:27-33 (1994)). For cellular immunotherapy, ROS production by human leukocytes is an important mechanism of tumor cell death in vitro (Clark and Klebanoff, J. Exp. Med. 141:1442-7 (1975) and Ackermann et al., Cancer Res. 49:52832 (1989)). In the foregoing techniques, ROS effectively kill tumor cells; however, ROS are also deposited within healthy tissues during anticancer therapy, thus causing substantial collateral damage (Chen et al., supra).
In PDT, a photosensitizing agent is administered to a target site in a subject and then irradiated by light of a certain wavelength, which activates the agent and induces the production of ROS to cause toxicity to nearby cells and tissue (see, e.g., U.S. Patent Publication No. 2010/0262115). Nanoparticles can be used as photosensitizing agents and are typically coupled with a chemotherapeutic agent to treat cancer. However, many nanoparticles require ultraviolet (UV) illumination having a wavelength less than 400 nm for activation. Consequently, their use in patient care is precluded by the fact that UV light promotes cancers, such as melanomas, and damage to the eye including pingueculae, cataracts, and other ocular disorders.
There is a need for therapeutic options able to deliver high ROS concentrations to target cells while minimizing damage to healthy tissues and other side effects.